As further background, bone grafting is commonly used to augment healing in the treatment of a broad range of musculoskeletal disorders. Grafting has been effective in reconstruction or replacement of bone defects, to augment fracture repair, to strengthen arthrodeses and to fill defects after treatment of tumors. Autograft techniques have been known for over 100 years and include the use of cortical and cancellous bone as grafting material. The use of autografts presents several serious drawbacks including the limited amount of potential donor material available, the requirement for two surgical intrusion sites on the patient, a high incidence of donor site morbidity, the tedious and complex nature of the techniques, particularly when vascularized grafts are involved, and the fact that donated bone can rarely be precisely sized or shaped to fit the needs of the implant site. Allografts can also be used in analogous procedures. Allografts have the benefits of avoiding two-site surgery on the patient and the elimination of donor site morbidity risk. However, allografts have increased risks of disease transmission and immunogenic implant rejection. Procedures used to reduce these new risks inherently decrease the viability of the allografts as effective implant material. Procedures with allografts also remain tedious and complex, suffer from limited source material and have the same limitations on sizing and shaping the implant to optimally fit the needs of the implant site.
A number of compositions have been developed to augment or replace autographic and allographic techniques to reduce or avoid the above mentioned drawbacks. Ceramics such as hydroxyapatite, tricalcium phosphate (TCP), and coralline hydroxyapatite have been shown to be beneficial osteoconductive matrices for use as fillers and/or expanders in bone graft material. Ceramics can add compression strength, but lack osteoinductive properties and, when used alone, lack shear and tensile strength. R. W. Bucholz, A. Carlson, R. E. Holmes, Hydroxyapatite and tricalcium phosphate bone graft substitutes. Orthop. Clin. North Am., Vol. 18(2), 1987, pg. 323-334 and R. W. Bucholz, A. Carlson, R. E. Holmes, Interporous hydroxyapatite as a bone graft substitute in tibial plateau fractures, Clin. Orthop., Vol. 240, 1989, pg. 53-62. Further, it has been shown in animal studies, that such ceramics can be filled with marrow to provide a beneficial level of initial progenitor cells and other osteogenic factors. H. Ohgushi, V. M. Goldberg, A. I. Caplan, Heterotopic osteogenesis in porous ceramics induced by marrow cells, J. Orthop. Res., Vol. 7, 1989, pg. 568-578.
The calcium phosphate based ceramics differ widely in their resorption characteristics once implanted. In addition to other factors, the resorption rate tends to increase with surface area of the ceramic, which in turn depends on the ceramic's particle shape, size, density and porosity. TCP is degraded 10-20 times faster than hydroxyapatite. Also partly as a result, if new bone development is established with a TCP implant, the TCP is generally remodeled better than hydroxyapatite in the final stage of bone formation. It is noteworthy that TCP is resorbed by osteoclast cells, whereas, the much slower resorption of hydroxyapatite is effected mainly by foreign-body giant cells. The giant cells have a limit as to the amount of hydroxyapatite they will resorb.
Pure ceramics do not offer optimum handling characteristics during implantation, but do offer excellent biocompatibility properties and tend to bond well to the existing bone. Ohgushi, et al. teaches the use of marrow infiltration of ceramics, while others have used various binders with granulated ceramics to formulate workable pastes that solidify to provide stable implants of desired shape and size. C. P. Desilets, L. J. Marden, A. L. Patterson and J. O. Hollinger, Development of synthetic bone-repair materials for craniofacial reconstruction, J. Craniofacial Surgery, Vol. 1(3), 1990, pg. 150-153.
Demineralized bone matrix (DBM) preparations have been researched extensively for use as bone implant material. DBM is prepared through the acid extraction of minerals from bone. It includes the collagen matrix of the bone together with acid insoluble proteins including bone morphogenic proteins (BMPs) and other growth factors. DBM can be processed as crushed granules, powder or chips. It can be formulated for use as granules, gels, sponge material or putty and can be freeze-dried for storage. Sterilization procedures required to protect from disease transmission may reduce the activity of beneficial growth factors in the DBM. DBM provides an initial osteoconductive matrix and exhibits a degree of osteoinductive potential, inducing the infiltration and differentiation of osteoprogenitor cells from the surrounding tissues. DBM lacks structural strength and is therefore only useful to fill well supported, stable skeletal defects such as cysts, simple fractures, and fillers for autographs and allographs. Examples of commercially available DBM products are Grafton® Allogenic Bone Matrix by Osteotech, Shrewbury, N.J., and Dynagraft® by Gensci Regeneration Laboratories, Irvine, Calif.
Various combinations of the above-mentioned bone implant materials have been made with a desire to obtain the benefits of the individual components without their individual drawbacks. Some combinations have met with a measure of success, but Y. Yamazaki, S. Shioda and S. Oida, Experimental Study on the Osteo-Induction Ability of Calcium Phosphate Biomaterials with added Bone Morphogenic Protein, Transaction of the Society for Biomaterials, 1986, pg. 111, teach that not all combinations of elements known to be individually beneficial for bone implant materials are additive in their beneficial characteristics or effective as composite implant materials. Yamazaki, et al. found that the osteoinductive potential of DBM and osteogenic protein extracts therefrom are inhibited by the addition of TCP or hydroxyapatite. No osteogenic composition has yet been found to be optimum in generalized usage and clinical results vary widely, even with seemingly well defined compositions. There remains a need for improved osteogenic implant materials that are consistently strongly osteoinductive, osteoconductive, easily workable in surgical procedures, and that provide strength and stability for new bone formation during the early stages of bone development, but are essentially completely incorporated and remodeled into bone by the end of the osteogenic process.
Compositions of mixed ceramics of TCP/hydroxyapatite and collagen are commercially available and can be enhanced by filling with autogenous bone marrow prior to implant. The composites are available as pastes or soft strips and tend to flow away from the implant site. The implant must therefore be carefully retained in place until the composite and any surrounding bleeding has fully clotted.
Compositions of bone gel known as GRAFTON® (see U.S. Pat. No. 5,481,601) comprising glycerol and DBM have been used singly and mixed with sand-like powder. Such compositions have been used to fill bone voids, cracks and cavities. GRAFTON® is available in flexible sheets or as a putty, thus making the composition more easily workable during implantation. Again, such compositions tend to flow away from the implant site.
Jefferies, in U.S. Pat. Nos. 4,394,370 and 4,472,840, teach a bone implant material composition of collagen and DBM or solubilized BMP that is optionally crosslinked with glutaraldehyde.
Caplan et al., in U.S. Pat. No. 4,620,327, describe the combination and partial immobilization by chemical cross-linking of soluble bone proteins with a number of solids to be implanted for bone repair/incorporation, including xenogenic bony implants, allografts, biodegradable masses and prosthetic devices to enhance new bone or cartilage formation. Ries et al., in U.S. Pat. No. 4,623,553, describe the glutaraldehyde or formaldehyde cross-linking of collagen and hydroxyapatite or TCP. Ries does not include any osteoinductive elements and is deemed only osteoconductive.
Some researchers have suggested the use of composites of TCP and/or biopolymers like polylactide, polyglycolide or their copolymers and particulate bone derivatives or BMP for craniofacial reconstruction. The TCP and biopolymers would provide a scaffold for new bone formation. The bone derivatives and BMP would induce osteogenesis beyond the slow, shallow osteoconduction induced by TCP and biopolymers alone. Desilets, et al.
Jefferies, in PCT WO 89/04646, describes osteoinductive implant materials having increased tensile strength by surface activating DBM or BMP with gluteraldehyde or other suitable cross-linking agent, followed by addition to a porous solid matrix where the activated DBM or BMP reacts with the solid to increase the cohesive strength of the composite. Jefferies also teaches the incorporation of therapeutic drugs into the matrix for the slow beneficial release thereof during the course of treatment.
In light of this background, there remain needs for improved osteogenic compositions and methods that effectively induce and support bone growth in mammals, including humans. The present invention is addressed to these needs.